PROJECT SUMMARY Currently, clinicians can offer little hope to people addicted to psychostimulants, such as methamphetamine (METH). The memories associated with drug use and reward can bear a powerful motivational influence over behavior. Accordingly, the field is now working to develop strategies to manipulate the extinction and reconsolidation of cue-drug associations as novel treatment strategies to reduce their power to induce craving and relapse. Here we propose to study the contribution of a novel class of candidates, long- noncoding RNAs (lncRNAs), to METH-associated memory. An increasing number of functional studies indicate lncRNAs participate as regulators at almost every stage of gene expression, from epigenetic modifications in the nucleus to mRNA stability and translation in the cytoplasm. This regulatory potential, along with the abundance of lncRNAs, implies that lncRNAs may be part of a broad epigenetic network. Despite these functional insights, only a small number of lncRNAs have been studied in the nervous system and their contribution to substance use disorder (SUD) is unknown. Because of the transcriptional and translational roles lncRNAs, elucidating their function in regions of brain implicated in SUD will help identify novel therapeutic targets. The central hypothesis of this proposal, derived from our own preliminary studies, is that specific lncRNAs mediate reconsolidation of METH-associated memories. To test this hypothesis, we will employ animal models of drug seeking and relapse to identify and manipulate specific lncRNAs in vivo with the goal of preventing relapse by blocking reconsolidation.